Triple monoamine reuptake inhibitors for the treatment of chronic pain

ABSTRACT

The present invention relates to the use of triple monoamine reuptake inhibitors for the treatment of chronic pain.

TECHNICAL FIELD

The present invention relates to the use of triple monoamine reuptakeinhibitors for the treatment of chronic pain.

BACKGROUND ART

Chronic pain conditions are debilitating diseases affecting at least5-10 percent of the population at some point in their lives. For thepatient suffering from a chronic pain disease, disturbance of, ordisruption to their daily life is almost inevitable with a greatlyincreased risk of developing comorbid psychiatric illness such asdepression.

Available drug treatments for chronic pain conditions are subject tovarious limitations. Non-steroidal anti-inflammatory drugs such asibuprofen and aspirin and opiates such as morphine, can be effective attreating chronic pain with a predominant inflammatory component, but aremuch less effective against chronic pain disorders associated with nervedamage (neuropathic pain). In addition the pain relief that can beobtained with opiates is often associated with tolerance and dependence,with increased risk of developing undesirable side effects.

Numerous random-controlled trials have shown that drugs capable ofmodulating monoamine transmission within the CNS such as the tricyclicantidepressant amitriptyline, are effective in the treatment of chronicpain. Whilst it is likely that inhibition of both noradrenaline andserotonin uptake within specific brainstem and forebrain areas isrequired to obtain analgesic efficacy, it has recently been reportedthat injection of a specific dopamine reuptake inhibitor into theforebrain can also inhibit the processing of pain (Burkey, A. R. et al.;J. Neurosci. (1999) 19 (10) 4169-4179).

Thus, although some chronic pain conditions are relatively well treatedat present, significant unmet needs remain. There is a continuedrequirement to develop more selective and effective therapies that arebetter tolerated, for the treatment of patients with chronic painconditions.

DETAILED DISCLOSURE OF THE INVENTION

It has now been found that a triple monoamine reuptake inhibitor isuseful in the treatment, prevention or alleviation of chronic pain.

Thus, in a first aspect the invention provides the use of a triplemonoamine reuptake inhibitor or a pharmaceutically acceptable saltthereof for the manufacture of a medicament for the treatment,prevention or alleviation of chronic pain.

In a second aspect, the invention provides a method for the treatment,prevention or alleviation of chronic pain in a subject, comprisingadministering to said subject a therapeutically effective amount of atriple monoamine reuptake inhibitor or a pharmaceutically acceptablesalt thereof.

In one embodiment, the triple monoamine reuptake inhibitor is a tropanederivative.

In a further embodiment, the triple monoamine reuptake inhibitor is acompound of the general formula I

or a pharmaceutically acceptable addition salt thereof or the N-oxidethereof, wherein

-   R is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl    or 2-hydroxyethyl;-   R³ is CH₂—X—R′,    -   wherein X is O, S, or NR″;-   wherein R″ is hydrogen or alkyl; and-   R′ is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, or    —CO-alkyl;-   R⁴ is    -   3,4-methylenedioxyphenyl or    -   phenyl, benzyl, naphthyl, or heteroaryl, each of which may be        substituted one or more times with substituents selected from        the group consisting of halogen, CF₃, CN, alkoxy, cycloalkoxy,        alkyl, cycloalkyl, alkenyl, alkynyl, amino, nitro, heteroaryl,        and aryl.

In a still further embodiment, the triple monoamine reuptake inhibitoris a 2,3-trans di-substituted tropane compound of the general formula I.In a further embodiment, the triple monoamine reuptake inhibitor is a(1R,2R,3S)-2,3-trans di-substituted tropane compound of the generalformula I.

In a still further embodiment, R is hydrogen or alkyl. In a specialembodiment, R is hydrogen. In a further embodiment, R is alkyl, such asmethyl.

In a further embodiment, R³ is CH₂—X—R′, wherein X is O or S, and R′ isalkyl, cycloalkyl or cycloalkylalkyl. In a special embodiment, R³ isCH₂—O—R′, wherein R′ is alkyl, cycloalkyl or cycloalkylalkyl. In aspecial embodiment, R′ is methyl, ethyl, isopropyl, orcyclopropylmethyl. In a further embodiment, R′ is methyl or ethyl.

In a further embodiment of the compound of general formula I, R⁴ isphenyl, which may be substituted one or more times with substituentsselected from the group consisting of halogen, CF₃, CN, alkoxy,cycloalkoxy, alkyl, cycloalkyl, alkenyl, alkynyl, amino, nitro, andheteroaryl. In a still further embodiment, R⁴ is phenyl, which may besubstituted one or more times with substituents selected from the groupconsisting of halogen, CF₃, and CN. In a special embodiment, R⁴ isphenyl substituted once or twice with halogen, such as chlorine. In afurther embodiment, R⁴ is 4-chlorophenyl. In a still further embodiment,R⁴ is 3,4-dichlorophenyl.

In a still further embodiment, the triple monoamine reuptake inhibitoris a 2,3-trans disubstituted tropane compound of general formula Iwherein

-   R is hydrogen, methyl, ethyl or propyl;-   R³ is —CH₂—X—R′, wherein X is O or S, and R′ is methyl, ethyl,    propyl, or cyclopropylmethyl; and-   R⁴ is phenyl, which may be substituted one or more times with    substituents selected from the group consisting of halogen, CF₃, and    CN.

In a further embodiment, the triple monoamine reuptake inhibitor is a2,3-trans disubstituted tropane compound of general formula I wherein

-   R is hydrogen or methyl;-   R³ is —CH₂—O—R′, wherein R′ is methyl, ethyl, propyl, or    cyclopropylmethyl; and-   R⁴ is phenyl, which may be substituted one or more times with    halogen.

In a still further embodiment, the triple monoamine reuptake inhibitoris a 2,3-trans disubstituted tropane compound of general formula Iwherein

-   R is hydrogen or methyl;-   R³ is —CH₂—O—R′, wherein R′ is methyl or ethyl; and-   R⁴ is 4-chlorophenyl or 3,4-dichlorophenyl.

In a special embodiment, the tropane derivative having dopamine reuptakeinhibitor activity is a compound of the general formula (I) selectedfrom:

-   (1R,2R,3S)-2-Methoxymethyl-3-(3,4-dichlorophenyl)-tropane;-   (1R,2R,3S)-2-Isopropoxymethyl-3-(3,4-dichlorophenyl)-tropane;-   (1R,2R,3S)-2-Ethoxymethyl-3-(3,4-dichlorophenyl)-tropane;-   (1R,2R,3S)-2-Cyclopropylmethyloxymethyl-3-(3,4-dichlorophenyl)-tropane;-   (1R,2R,3S)-2-Methoxymethyl-3-(4-chlorophenyl)-tropane;-   (1R,2R,3S)-N-Normethyl-2-methoxymethyl-3-(4-chlorophenyl)-tropane;-   (1R,2R,3S)-2-Ethoxymethyl-3-(4-chlorophenyl)-tropane;-   (1R,2R,3S)-N-Normethyl-2-methoxymethyl-3-(3,4-dichlorophenyl)-tropane;-   (1R,2R,3S)-N-Normethyl-2-ethoxymethyl-3-(3,4-dichlorophenyl)-tropane;-   (1R,2R,3S)-N-Normethyl-2-ethoxymethyl-3-(4-chlorophenyl)-tropane;-   (1R,2R,3S)-N-Normethyl-2-cyclopropylmethyloxymethyl-3-(4-chlorophenyl)-tropane;-   (1R,2R,3S)-2-Cyclopropylmethyloxymethyl-3-(4-chlorophenyl)-tropane;-   (1R,2R,3S)-2-Ethylthiomethyl-3-(3,4-dichlorophenyl)-tropane;-   (1R,2R,3S)-2-Hydroxymethyl-3-(4-fluorophenyl)tropane;-   (1R,2R,3S)-2-Hydroxymethyl-3-(3,4-dichlorophenyl)tropane;-   (1R,2R,3S)-2-Hydroxymethyl-3-(4-chlorophenyl)tropane;    or a pharmaceutically acceptable addition salt thereof.

In a further embodiment, the chronic pain is inflammatory pain,neuropathic pain, fibromyalgia, chronic fatigue syndrome, tension-typeheadache or any pain arising as a consequence of or associated withdepressive illness. In a special embodiment, the chronic pain isinflammatory pain. In a further embodiment, the chronic pain isneuropathic pain. In a still further embodiment, the chronic pain isfibromyalgia. In a further embodiment, the chronic pain is chronicfatigue syndrome. In a still further embodiment, the chronic pain istension-type headache. In a further embodiment, the chronic pain is anypain arising as a consequence of or associated with depressive illness.

Triple Monoamine Reuptake Inhibitor

A triple monoamine reuptake inhibitor is a compound that inhibits thereuptake of the three monoamines serotonin, noradrenaline, and dopamine.

The potential of a given substance to act as a triple monoamine dopaminereuptake inhibitors activity may be determined using standard in vitrobinding assays and/or standard in vivo functionality tests.

The triple monoamine reuptake inhibitors for use according to theinvention may in particular be tropane derivatives such as thosedisclosed in WO 97/30997 (NeuroSearch A/S).

In one embodiment, the triple monoamine reuptake inhibitor shows IC₅₀values of less than 100 nM, preferably less than 50 nM, and morepreferably less than 10 nM for each of the monoamines dopamine,serotonin, and noradrenaline when tested for in vitro inhibitionaccording to standard test methods.

In a second embodiment, the triple monoamine reuptake inhibitor showsED₅₀ value of less than 50 mg/kg, preferably less than 10 mg/kg, morepreferably less than 5 mg/kg for each of the monoamines dopamine,serotonin, and noradrenaline when tested for in vivo inhibitionaccording to standard test methods.

The above examples of triple monoamine reuptake inhibitors are notintended to be in any way limiting to the scope of the invention asclaimed.

Chronic Pain Conditions

In the context of the present invention, the term “chronic pain”includes inflammatory pain, neuropathic pain, fibromyalgia, chronicfatigue syndrome, chronic tension-type headache, and any pain arising asa consequence of or associated with depressive illness.

Inflammatory pain includes without limitation, osteoarthritis,rheumatoid arthritis, back pain, cancer pain, irritable bowel pain,post-operative pain, pain associated with viral infection or diseaseswith a recognised peripheral or central inflammatory component.

Neuropathic pain includes without limitation, pain arising from anydisease state causing damage to the peripheral or central nervoussystems, back pain, cancer pain, chemotherapy induced neuropathy,irritable bowel pain, post-stroke pain, post-operative pain,sympathetically-maintained pain, phantom-limb pain, pain associated withviral infection such as postherpetic neuralgia, trigeminal neuralgia,dental pain, myofacial pain, diabetic neuropathy, pain associated withautoimmune disease such as HIV infection and multiple sclerosis,phantom-limb pain, arthritis, or drug-induced neuropathy.

Definition of Substituents

In the context of this invention alkyl designates a straight chain or abranched chain containing of from one to six carbon atoms (C₁-C₆ alkyl),including but not limited to methyl, ethyl, propyl, isopropyl, butyl,isobutyl, t-butyl, pentyl and hexyl. In a preferred embodiment of thisinvention alkyl represents a C₁-C₄ alkyl, preferably a C₁-C₃ alkyl, mostpreferred methyl, ethyl, propyl or isopropyl.

In the context of this invention cycloalkyl designates a cyclic alkylcontaining of from three to seven carbon atoms (C₃-C₇ cycloalkyl),including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, andcyclohexyl.

In the context of this invention alkenyl designates a group containingof from two to six carbon atoms (C₂-C₆ alkenyl), including at least onedouble bond, for example, but not limited to ethenyl, 1,2- or2,3-propenyl, 1,2-, 2,3-, or 3,4-butenyl.

In the context of this invention alkynyl designates a group containingof from two to six carbon atoms (C₂-C₆ alkynyl), including at least onetriple bond, for example, but not limited to ethynyl, 1,2- or2,3-propynyl, 1,2-, 2,3- or 3,4-butynyl.

In the context of this invention cycloalkylalkyl designates a cycloalkylas defined above which is attached to an alkyl as also defined above,e.g. cyclopropylmethyl.

In the context of this invention aryl designates an aromatichydrocarbon, such as phenyl or naphthyl.

In the context of this invention alkoxy designates an alkyl-O—, wherealkyl is as defined above.

In the context of this invention halogen designates a fluorine, achlorine, a bromine or an iodine atom.

In the context of this invention amino represents NH₂, NH-alkyl, orN-(alkyl)₂, wherein alkyl is as defined above.

In the context of this invention heteroaryl designates a 5- or6-membered heterocyclic monocyclic group, for example, but not limitedto, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isoxazol-3-yl, isoxazol-4-yl,isoxazol-5-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl,isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, 1,2,4-oxadiazol-3-yl,1,2,4-oxadiazol-5-yl, 1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl,1,2,5-oxadiazol-3-yl, 1,2,5-oxadiazol-4-yl, 1,2,5-thiadiazol-3-yl,1,2,5-thiadiazol-4-yl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl,2-pyrrolyl, 3-pyrrolyl, 2-furanyl, 3-furanyl, 2-thienyl, 3-thienyl,2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl,5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrazinyl, 1-pyrazolyl,3-pyrazolyl, and 4-pyrazolyl.

Steric Isomers

The chemical compounds for use in the invention may exist in (+) and (−)forms as well as in racemic forms. The use of racemates of these isomersand the individual isomers themselves are within the scope of thepresent invention.

Racemic forms can be resolved into the optical antipodes by knownmethods and techniques. One way of separating the diastereomeric saltsis by use of an optically active acid, and liberating the opticallyactive amine compound by treatment with a base. Another method forresolving racemates into the optical antipodes is based uponchromatography on an optical active matrix. Racemic compounds of thepresent invention can thus be resolved into their optical antipodes,e.g., by fractional crystallisation of d- or l-(tartrates, mandelates,or camphorsulphonate) salts for example.

The chemical compounds for use in the invention may also be resolved bythe formation of diastereomeric amides by reaction of the chemicalcompounds of the present invention with an optically active activatedcarboxylic acid such as that derived from (+) or (−) phenylalanine, (+)or (−) phenylglycine, (+) or (−) camphanic acid or by the formation ofdiastereomeric carbamates by reaction of the chemical compound of thepresent invention with an optically active chloroformate or the like.

Additional methods for the resolving the optical isomers are known inthe art. Such methods include those described by Jaques J, Collet A, &Wilen S in “Enantiomers, Racemates, and Resolutions”, John Wiley andSons, New York (1981).

Moreover, some of the chemical compounds for use in the invention maythus exist in two forms, syn- and anti-form (Z- and E-form), dependingon the arrangement of the substituents around a —C═C— or —C═N— doublebond. A chemical compound for use according to the present invention maythus be the syn- or the anti-form (Z- and E-form), or it may be amixture hereof.

Pharmaceutically Acceptable Salts

The triple monoamine reuptake inhibitor for use according to theinvention may be provided in any form suitable for the intendedadministration. Suitable forms include pharmaceutically (i.e.physiologically) acceptable salts, and pre- or prodrug forms of thechemical compound for use according to the invention.

Examples of pharmaceutically acceptable addition salts include, withoutlimitation, the non-toxic inorganic and organic acid addition salts suchas the hydrochloride derived from hydrochloric acid, the hydrobromidederived from hydrobromic acid, the nitrate derived from nitric acid, theperchlorate derived from perchloric acid, the phosphate derived fromphosphoric acid, the sulphate derived from sulphuric acid, the formatederived from formic acid, the acetate derived from acetic acid, theaconate derived from aconitic acid, the ascorbate derived from ascorbicacid, the benzenesulphonate derived from benzensulphonic acid, thebenzoate derived from benzoic acid, the cinnamate derived from cinnamicacid, the citrate derived from citric acid, the embonate derived fromembonic acid, the enantate derived from enanthic acid, the fumaratederived from fumaric acid, the glutamate derived from glutamic acid, theglycolate derived from glycolic acid, the lactate derived from lacticacid, the maleate derived from maleic acid, the malonate derived frommalonic acid, the mandelate derived from mandelic acid, themethanesulphonate derived from methane sulphonic acid, thenaphthalene-2-sulphonate derived from naphtalene-2-sulphonic acid, thephthalate derived from phthalic acid, the salicylate derived fromsalicylic acid, the sorbate derived from sorbic acid, the stearatederived from stearic acid, the succinate derived from succinic acid, thetartrate derived from tartaric acid, the toluene-p-sulphonate derivedfrom p-toluene sulphonic acid, and the like. Such salts may be formed byprocedures well known and described in the art.

Metal salts of a chemical compound for use according to the inventioninclude alkali metal salts such as the sodium salt of the chemicalcompound containing a carboxy group.

The term “prodrug” denotes a compound, which is a drug precursor andwhich, following administration and absorption, release the drug in vivovia some metabolic process.

Particularly favoured prodrugs are those that increase thebioavailability of the compounds for use according to the invention(e.g. by allowing an orally administrered compound to be more readilyabsorbed into the blood) or which enhance delivery of the parentcompound to a specific biological compartment (e.g. the brain orlymphatic system).

Thus examples of suitable prodrugs of the substances according to theinvention include compounds modified at one or more reactive orderivatizable groups of the parent compound. Of particular interest arecompounds modified at a carboxyl group, a hydroxyl group, or an aminogroup. Examples of suitable derivatives are esters or amides.

Pharmaceutical Compositions

The invention provides the use of pharmaceutical compositions comprisinga therapeutically effective amount of the triple monoamine reuptakeinhibitor. While a triple monoamine reuptake inhibitor for use intherapy according to the invention may be administered in the form ofthe raw chemical compound, it is preferred to introduce the activeingredient, optionally in the form of a physiologically acceptable salt,in a pharmaceutical composition together with one or more adjuvants,excipients, carriers, buffers, diluents, and/or other customarypharmaceutical auxiliaries.

In a preferred embodiment, the invention provides pharmaceuticalcompositions comprising the triple monoamine reuptake inhibitor,together with one or more pharmaceutically acceptable carrierstherefore, and, optionally, other therapeutic and/or prophylacticingredients, know and used in the art. The carrier(s) must be“acceptable” in the sense of being compatible with the other ingredientsof the formulation and not harmful to the recipient thereof.

Pharmaceutical compositions for use according to the invention may bethose suitable for oral, rectal, bronchial, nasal, pulmonal, topical(including buccal and sub-lingual), transdermal, vaginal or parenteral(including cutaneous, subcutaneous, intramuscular, intraperitoneal,intravenous, intraarterial, intracerebral, intraocular injection orinfusion) administration, or those in a form suitable for administrationby inhalation or insufflation, including powders and liquid aerosoladministration, or by sustained release systems. Suitable examples ofsustained release systems include semipermeable matrices of solidhydrophobic polymers containing the compound of the invention, whichmatrices may be in form of shaped articles, e.g. films or microcapsules.

The chemical compound for use according to the invention, together witha conventional adjuvant, carrier, or diluent, may thus be placed intothe form of pharmaceutical compositions and unit dosages thereof. Suchforms include solids, and in particular tablets, filled capsules, powderand pellet forms, and liquids, in particular aqueous or non-aqueoussolutions, suspensions, emulsions, elixirs, and capsules filled with thesame, all for oral use, suppositories for rectal administration, andsterile injectable solutions for parenteral use. Such pharmaceuticalcompositions and unit dosage forms thereof may comprise conventionalingredients in conventional proportions, with or without additionalactive compounds or principles, and such unit dosage forms may containany suitable effective amount of the active ingredient commensurate withthe intended daily dosage range to be employed.

The chemical compound for use according to the present invention can beadministered in a wide variety of oral and parenteral dosage forms. Itwill be obvious to those skilled in the art that the following dosageforms may comprise, as the active component, either a chemical compoundof the invention or a pharmaceutically acceptable salt of a chemicalcompound of the invention.

For preparing pharmaceutical compositions from a chemical compound foruse according to the present invention, pharmaceutically acceptablecarriers can be either solid or liquid. Solid form preparations includepowders, tablets, pills, capsules, cachets, suppositories, anddispersible granules. A solid carrier can be one or more substanceswhich may also act as diluents, flavouring agents, solubilizers,lubricants, suspending agents, binders, preservatives, tabletdisintegrating agents, or an encapsulating material.

In powders, the carrier is a finely divided solid, which is in a mixturewith the finely divided active component.

In tablets, the active component is mixed with the carrier having thenecessary binding capacity in suitable proportions and compacted in theshape and size desired.

The powders and tablets preferably contain from five or ten to aboutseventy percent of the active compound. Suitable carriers are magnesiumcarbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin,starch, gelatin, tragacanth, methylcellulose, sodiumcarboxymethylcellulose, a low melting wax, cocoa butter, and the like.The term “preparation” is intended to include the formulation of theactive compound with encapsulating material as carrier providing acapsule in which the active component, with or without carriers, issurrounded by a carrier, which is thus in association with it.Similarly, cachets and lozenges are included. Tablets, powders,capsules, pills, cachets, and lozenges can be used as solid formssuitable for oral administration.

For preparing suppositories, a low melting wax, such as a mixture offatty acid glyceride or cocoa butter, is first melted and the activecomponent is dispersed homogeneously therein, as by stirring. The moltenhomogenous mixture is then poured into convenient sized moulds, allowedto cool, and thereby to solidify.

Compositions suitable for vaginal administration may be presented aspessaries, tampons, creams, gels, pastes, foams or sprays containing inaddition to the active ingredient such carriers as are known in the artto be appropriate.

Liquid preparations include solutions, suspensions, and emulsions, forexample, water or water-propylene glycol solutions. For example,parenteral injection liquid preparations can be formulated as solutionsin aqueous polyethylene glycol solution.

The chemical compound for use according to the present invention maythus be formulated for parenteral administration (e.g. by injection, forexample bolus injection or continuous infusion) and may be presented inunit dose form in ampoules, pre-filled syringes, small volume infusionor in multi-dose containers with an added preservative. The compositionsmay take such forms as suspensions, solutions, or emulsions in oily oraqueous vehicles, and may contain formulation agents such as suspending,stabilising and/or dispersing agents. Alternatively, the activeingredient may be in powder form, obtained by aseptic isolation ofsterile solid or by lyophilization from solution, for constitution witha suitable vehicle, e.g. sterile, pyrogen-free water, before use.

Aqueous solutions suitable for oral use can be prepared by dissolvingthe active component in water and adding suitable colorants, flavours,stabilising and thickening agents, as desired.

Aqueous suspensions suitable for oral use can be made by dispersing thefinely divided active component in water with viscous material, such asnatural or synthetic gums, resins, methylcellulose, sodiumcarboxymethylcellulose, or other well known suspending agents.

Also included are solid form preparations, intended for conversionshortly before use to liquid form preparations for oral administration.Such liquid forms include solutions, suspensions, and emulsions. Inaddition to the active component such preparations may comprisecolorants, flavours, stabilisers, buffers, artificial and naturalsweeteners, dispersants, thickeners, solubilizing agents, and the like.

For topical administration to the epidermis the chemical compound of theinvention may be formulated as ointments, creams or lotions, or as atransdermal patch. Ointments and creams may, for example, be formulatedwith an aqueous or oily base with the addition of suitable thickeningand/or gelling agents. Lotions may be formulated with an aqueous or oilybase and will in general also contain one or more emulsifying agents,stabilising agents, dispersing agents, suspending agents, thickeningagents, or colouring agents.

Compositions suitable for topical administration in the mouth includelozenges comprising the active agent in a flavoured base, usuallysucrose and acacia or tragacanth; pastilles comprising the activeingredient in an inert base such as gelatin and glycerine or sucrose andacacia; and mouthwashes comprising the active ingredient in a suitableliquid carrier.

Solutions or suspensions are applied directly to the nasal cavity byconventional means, for example with a dropper, pipette or spray. Thecompositions may be provided in single or multi-dose form.

Administration to the respiratory tract may also be achieved by means ofan aerosol formulation in which the active ingredient is provided in apressurised pack with a suitable propellant such as a chlorofluorocarbon(CFC) for example dichlorodifluoromethane, trichlorofluoromethane, ordichlorotetrafluoroethane, carbon dioxide, or other suitable gas. Theaerosol may conveniently also contain a surfactant such as lecithin. Thedose of drug may be controlled by provision of a metered valve.

Alternatively the active ingredients may be provided in the form of adry powder, for example a powder mix of the compound in a suitablepowder base such as lactose, starch, starch derivatives such ashydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP).Conveniently the powder carrier will form a gel in the nasal cavity. Thepowder composition may be presented in unit dose form for example incapsules or cartridges of, e.g., gelatin, or blister packs from whichthe powder may be administered by means of an inhaler.

In compositions intended for administration to the respiratory tract,including intranasal compositions, the compound will generally have asmall particle size for example of the order of 5 microns or less. Sucha particle size may be obtained by means known in the art, for exampleby micronization.

When desired, compositions adapted to give sustained release of theactive ingredient may be employed.

The pharmaceutical preparations are preferably in unit dosage forms. Insuch form, the preparation is subdivided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, such as packaged tablets, capsules, and powders in vials orampoules. Also, the unit dosage form can be a capsule, tablet, cachet,or lozenge itself, or it can be the appropriate number of any of thesein packaged form.

Tablets or capsules for oral administration and liquids for intravenousadministration and continuous infusion are preferred compositions.

Further details on techniques for formulation and administration may befound in the latest edition of Remington's Pharmaceutical Sciences(Maack Publishing Co., Easton, Pa.).

The actual dosage depend on the nature and severity of the disease beingtreated, and is within the discretion of the physician, and may bevaried by titration of the dosage to the particular circumstances ofthis invention to produce the desired therapeutic effect. However, it ispresently contemplated that pharmaceutical compositions containing offrom about 0.1 to about 500 mg of active ingredient per individual dose,preferably of from about 1 to about 100 mg, most preferred of from about1 to about 10 mg, are suitable for therapeutic treatments.

Methods of Therapy

In another aspect the invention provides method for the treatment,prevention or alleviation of chronic pain in a subject, comprisingadministering to said subject a therapeutically effective amount of atriple monoamine reuptake inhibitor or a pharmaceutically acceptablesalt thereof.

The active ingredient may be administered in one or several doses perday. A satisfactory result can, in certain instances, be obtained at adosage as low as 0.1 μg/kg i.v. and 1 μg/kg p.o. The upper limit of thedosage range is presently considered to be about 10 mg/kg i.v. and 100mg/kg p.o. Preferred ranges are from about 0.1 μg/kg to about 10mg/kg/day i.v., and from about 1 μg/kg to about 100 mg/kg/day p.o.

Methods of Preparation

The compounds of general formula (I) for use in the invention may beprepared by conventional methods of chemical synthesis, e.g. thosedescribed WO 97/30997 (NeuroSearch A/S).

The starting materials for the processes described in the presentapplication are known or may readily be prepared by conventional methodsfrom commercially available chemicals.

The end products of the reactions described herein may be isolated byconventional techniques, e.g. by extraction, crystallisation,distillation, chromatography, etc.

Any possible combination of two or more of the embodiments described inthis patent application is comprised within the scope of the presentinvention.

1. A method for the treatment or alleviation of a chronic pain conditionin a subject comprising: administering to said subject a therapeuticallyeffective amount of a triple monoamine reuptake inhibitor wherein thetriple monoamine reuptake inhibitor is a compound of formula (I)

 or a pharmaceutically acceptable addition salt thereof or the N-oxidethereof, wherein the chronic pain condition is selected from at leastone of the group of chronic pain conditions consisting of: inflammatorypain, neuropathic pain, fibromyalgia and tension-type headache, andwherein R is hydrogen or methyl; R³is —CH₂—O—R′, wherein R′ is methyl,ethyl or propyl; and R⁴is 3,4-dichlorophenyl.
 2. The method according toclaim 1, wherein the tropane derivative is selected from(1R,2R,3S)-2-Methoxymethyl-3-(3,4-dichlorophenyl)-tropane;(1R,2R,3S)-2-Isopropoxymethyl-3-(3,4-dichlorophenyl)-tropane;(1R,2R,3S)-2-Ethoxymethyl-3-(3,4-dichlorophenyl)-tropane;(1R,2R,3S)-N-Normethyl-2-methoxymethyl-3-(3,4-dichlorophenyl)-tropane;(1R,2R,3S)-N-Normethyl-2-ethoxymethyl-3-(3,4-dichlorophenyl)-tropane; ora pharmaceutically acceptable addition salt thereof.
 3. The methodaccording to claim 1, wherein R′ is ethyl.
 4. The method according toclaim 1, wherein the tropane derivative is selected from:(1R,2R,3S)-2-Ethoxymethyl-3-(3,4-dichlorophenyl)-tropane;(1R,2R,3S)-N-Normethyl-2-ethoxymethyl-3-(3,4-dichlorophenyl)-tropane; ora pharmaceutically acceptable addition salt thereof.
 5. A method for thetreatment or alleviation of a chronic pain condition in a subjectcomprising: administering to said subject a therapeutically effectiveamount of (1R,2R,3S)-2-Ethoxymethyl-3-(3,4-dichlorophenyl)-tropane; or apharmaceutically acceptable addition salt thereof, wherein the chronicpain condition is selected from at least one of the group of chronicpain conditions consisting of: inflammatory pain, neuropathic pain,fibromyalgia and tension-type headache.
 6. A method for the treatment oralleviation of a chronic pain condition in a subject comprising:administering to said subject a therapeutically effective amount of(1R,2R,3S)-N-Normethyl-2-methoxymethyl-3-(3,4-dichlorophenyl)-tropane;or a pharmaceutically acceptable addition salt thereof, wherein thechronic pain condition is selected from at least one of the group ofchronic pain conditions consisting of: inflammatory pain, neuropathicpain, fibromyalgia and tension-type headache.